Methods for preparing macrocyclic products by ring-closing diyne metathessis

ABSTRACT

The present invention relates to methods for preparing macrocyclic products having 9 or more ring atoms by ring-closing diyne metathesis of suitable diyne substrates. The diyne substrates can be converted into cycloalkynes or into cycloalkadiynes by cyclodimerization, depending on the particular reaction conditions. Any alkyne metathesis catalyst can be used as the catalyst, regardless of whether said catalysts are heterogeneously or homogeneously present in the reaction medium. The preferred catalysts or pre-catalysts are transition metal alkylidyne complexes, transition metal compounds which form alkylidyne complexes under the reaction conditions, and transition metal compounds with metal-metal triple bonds. The method can be carried out with numerous functional groups, solvents, and additives. Using known methods, the formed macrocyclic cycloalkynes or cycloalkadiynes can be converted into numerous secondary products, especially macrocyclic cycloalkenes with a uniform configuration of the double bond, and used, e.g., for the synthesis of epothilone or epothilone analogues.

This application is a 371 of PCT/EP99/00674, filed on Feb. 2, 1999.

The present invention pertains to methods for preparing macrocyclicproducts having 9 or more ring atoms by a ring-closing metathesis ofdiyne substrates.

By alkyne metathesis there is understood the mutual transalkylidynationof alkynes according to scheme 1.

Usually, reactions of this type are catalyzed by metal compounds(reviews: Schrock, R. R. Polyhedron 1995, 14, 3177; Ivin, K. J.; Mol, J.C. Olefin Metathesis and Metathesis Polymerization, Academic Press, NewYork, 1997, p 192-223). Contrary to the metathesis of alkenes, which isa well-established field of research today and has found numerousapplications in the preparation of technically important products(reviews: Ivin, K. J.; Mol, J. C. Olefin Metathesis and MetathesisPolymerization, Academic Press, New York, 1997; Schuster, M. et al.,Angew. Chem. 1997, 109, 2125), in organic chemistry the application ofthe alkyne metathesis is restricted to the preparation of specialpolymers (Weiss, K. et al., Angew. Chem. 1997, 109, 522), thering-opening polymerization of cycloalkynes (Krouse, S. A. et al.,Macromolecules 1989, 22, 2569; Zhang, X-P. et al., Macromolecules 1994,27, 4627) and the dimerization or the cross metathesis of acyclicalkynes (Kaneta, N. et al., Chem. Lett. 1995, 1055; Sancho, J. et al.,J. Mol. Cat. 1982, 15, 75; Villemin, D. et al., Tetrahedron Lett 1982,5139). The metatheses of diynes result in polymeric products by acyclicdiyne metathesis (Krouse, S. A. et al., Macromolecules 1989, 22, 2569)or by cyclopolymerization (Fox, H. H. et al. J. Am. Chem. Soc. 1994,116, 2827; Koo, K.-M. et al., Macromolecules 1993, 26, 2485).

Both heterogeneous and homogeneous transition metal compounds can beused as catalysts or pre-catalysts for alkyne metatheses. Transitionmetal alkylidyne complexes and transition metal carbyne complexes whichmay either be added to the reaction mixtures in isolated form or formedin situ from suitable pre-catalysts are regarded as catalytically activespecies (Katz, T. J. et al., J. Am. Chem. Soc. 1975, 97, 1592). Thecatalytic activity of transition metal compounds in alkyne metathesescan be increased by the addition of suitable additives such as, e.g.,phenol derivatives (Mortreux, A. et al., J. Chem. Soc. Chem. Commun.1974, 786; Mortreux, A. et al., J. Mol. Cat. 1977, 2, 73; Villemin, D.et al., Tetrahedron Lett. 1982, 5139), aluminium alkyls (Petit, M. etal., J. Chem. Soc. Chem. Commun. 1982, 1385), or SiO₂ (Mortreux, A. etal., Bull. Soc. Chim. Fr. 1972, 1641; Mortreux, M. et al. J. Mol. Cat.1980, 8, 97).

Preferred catalysts or pre-catalysts for alkyne metatheses are Mo(CO)₆(Mortreux, A. et al., J. Chem. Soc. Chem. Commun. 1974, 786; Mortreux,A. et al., J. Mol. Cat. 1977, 2, 73; Villemin, D. et al, TetrahedronLett 1982, 5139; Tsonis, C. React. Kinet. Catal. Lett. 1992, 46, 359),MoO₂(acac)₂/Et₃Al (Petit, M. et al., J. Chem. Soc, Chem. Commun. 1982,1385), MoO₃/SiO₂ (Mortreux, A. et al., Bull. Soc. Chim. Fr. 1972, 1641;Mortreux, M. et al. J. Mol. Cat. 1980, 8, 97), WoO₃/SiO₂ (Pennella, F.et al., Chem, Commun 1968, 1548), W(≡CCMe₃)(OR)₃ or Mo(≡CCMe₃)(OR)₃[R═CMe₃, CH(CF₃)₂, CMe₂CF₃, CMe(CF₃)₂, C(CF₃)₃, C₆H₃Me₂, C₆H₃i-Pr₂,C₆H₃t-Bu₂] (Review: Schrock, R. R., Polyhedron 1995, 14, 3177; Sancho,J. et al., J. Mol. Cat. 1982, 15, 75; Weiss, K. in Carbyne Complexes[Fischer, H. et al., Eds.], Verlag Chemie, Weinheim, 1988, p 220),Re(≡CCMe₃)(═NAr)[OCMe(CF₃)₂]₂ (Schrock, R. R. et al., J. Am. Chem. Soc.1988, 110, 2686; Weinstock, I. A. et al., J. Am. Chem, Soc. 1991, 113,135), (Me₃CO)₃W≡W(OCMe₃) or (Me₃CO)₃Mo≡Mo(OCMe₃) (Schrock, R. R.Polyhedron 1995, 14, 3177; Krouse, S. A. et al., Macromolecules 1989,22, 2569; Zhang, X-P. et al., Macromolecules 1994, 27, 4627) andcomplexes containing a Re≡Re triple bond (Diefenbach, S. P. U.S. Pat.No. 4,698,451, 06. Okt. 1987; Chem. Abstr. 1988, 108, 40092 m).

In the literature both diynes and cycloalkynes have only been used asstarting materials for polymerization reactions via alkyne metathesis.Surprisingly, however, we have found that diynes having suitable chainlengths used as substrates can be closed in the presence of suitablecatalysts with a high selectivity to yield cycloalkynes, provided theformed cycloalkynes have 12 or more ring atoms (scheme 2).

Furthermore, it turned out that diynes having suitable chain lengths andused as substrates can also be closed with high selectivity to yieldcycloalkynes having from 9-11 ring atoms, provided the diyne substratesare conformationally pre-organized for the ring closure by one orseveral structural elements. Said structural elements comprise rigidbackbones, annellated rings, pre-existing double bonds, hydrogen bonds,geminal dialkyl groups, a coordination at metal centers, chiral centers,supramolecular structures.

This access to said class of substances, which is improved and shortenedas compared with the previously used methods for preparing cycloalkynes,is important since various cycloalkynes as such are interesting asantibiotics (confer Nicolauo K. C. Angew. Chem. 1991, 103, 1453) and canbe converted into other macrocyclic products of economic importance suchas, e.g., pharmaceuticals, pheromones, agrochemicals, crown ethers,odorous substances, perfume ingredients, or flavoring agents by existingmethods.

The selectivity of this reaction depends in particular on the structureof the substrates, the used catalyst, the reaction conditions, and thering strain within the prepared cycloalkyne. The formation of thecycloalkynes is favored by performing the reaction under high dilutionin an organic solvent which does not deactivate the catalyst. Whendetermining the concentration of the substrate in the reaction medium,the effective molarity parameter thereof has to be considered(Mandolini, L. Adv. Phys. Org. Chem. 1986, 22, 1). According to thepresent invention, cycloalkadiyne products can also be obtained athigher concentrations by a cyclodimerization of the diyne substratesaccording to scheme 3.

In the present invention all metal compounds being active in alkynemetatheses may be catalysts or pre-catalysts regardless of whether theyare initially introduced homogeneously or heterogeneously into thereaction medium. The catalysts can be employed in an isolated form orformed in situ within the reaction medium from suitable precursors. Theused amount of catalyst is not critical, with preferred amounts ofcatalyst being within the range from 0.01-10%, based on the usedsubstrate.

Transition metal alkylidyne complexes, transition metal compoundsforming alkylidyne complexes under reaction conditions, and transitionmetal compounds with metal-metal triple bonds are preferred catalysts orpre-catalysts.

The abbreviations used in the following text indicate: i-Pr=isopropyl;t-Bu=tertiary butyl; Ph=phenyl; acac=acetylacetonate; Ar=aryl;gem=geminal; Me=methyl.

Complexes of the general type M(≡CR¹)(OR²)₃ with

M=Mo, W

R¹=C₁-C₂₀ alkyl, aryl, alkenyl, alkylthio, dialkylamino, preferablyCMe₃, Ph

R²=C₁-C₂₀ alkyl, aryl, preferably CMe₃, CH(CF₃)₂, CMe₂CF₃, CMe(CF₃)₂,C(CF₃)₃, C₆H₃Me₂, C₆H₃i-Pr₂, C₆H₃t-Bu₂ are especially preferredcatalysts or pre-catalysts.

Especially preferred catalysts or pre-catalysts are also complexes ofthe general type Re(≡CR¹)(═NAr)(OR²)₂ with

R¹=C₁-C₂₀ alkyl, aryl, alkenyl, preferably CMe₃, Ph

Ar=C₆-C₂₀ aryl

R²=C₁-C₂₀ alkyl, aryl, preferably CMe₃, CH(CF₃)₂, CMe₂CF₃, CMe(CF₃)₂,C(CF₃)₃, C₆H₃Me₂, C₆H₃i-Pr₂, C₆H₃t-Bu₂

Especially preferred catalysts or pre-catalysts are also complexes ofthe general type (RO)₃M≡M(OR)₃ with

M=Mo, W

R=C₁-C₂₀ alkyl, aryl, preferably CMe₃, CH(CF₃)₂, CMe₂CF₃, CMe(CF₃)₂,C(CF₃)₃.

Preferred catalysts formed in situ within the reaction medium resultfrom mixtures of Mo(CO)₆ and phenols. Especially preferred catalysts areformed by using electron-deficient phenols such astrifluoromethylphenolf bis(trifluoromethyl)phenol, fluorophenol,difluorophenol, pentafluorophenol, chlorophenol, dichlorophenolntachlorophenol. The ratio Mo(CO)₆: phenol is not critical; preferredratios Mo(CO)₆: phenol are within the range from 1:1 to 1:1000.

Furthermore, preferred catalysts produced in situ within the reactionmedium are formed from mixtures of M[N(R¹)Ar]₃ and halogen compounds ofthe R² ₂EX₂ or R³ ₃SiX types, wherein

M=Mo, W p1 R¹=C₁-C₂₀ alkyl, secondary alkyl (sec-alkyl), tertiary alkyl(t-alkyl), cycloalkyl, preferably t-Bu

Ar=C₆-C₂₀ aryl, preferably C₆H₅, C₆H₄Me, C₆H₃Me₂, C₆H₃(i-Pr)₂,C₆H₃(t-Bu)₂, C₆H₂Me₃

R²=H, F, Cl, Br, I, C₁₋₂₀ alkyl, aryl

E=C, Si

R³=C₁-C₂₀ alkyl, aryl, preferably methyl

X=F, Cl, Br, I

With respect to compounds of the M[N(R¹)Ar]₃ type see: C. E. Laplaza etal., J. Am. Chem. Soc. 1996, 118, 8623.

The diynes used in the present invention as substrates may contain oneor several functional groups in the form of substituents on the chain orheteroatoms within the chain. Said substituents comprise inter aliabranched or unbranched alkyl rests, aromatic or non-aromatic carbocyclicrings, aromatic or non-aromatic nitrogen, oxygen, sulfur, or phosphorouscontaining heterocyclic rings, carboxylic acids, esters, ethers,epoxides, silyl ethers, thioethers, thioacetals, disulfides, alcohols,anhydrides, imines, silyl ethers, silylenol ethers, ammonium salts,amines, amides, nitriles, perfluoroalkyl groups, gem-dialkyl groups,alkenes, halogens, ketones, ketals, aldehydes, acetals, carbamates,carbonates, urethanes, ureas, sulfonates, sulfones, sulfonamides,sulfoxides, phosphates, phosphonates, nitro groups, organosilanemoieties, or metal centers. The presence of said functional groupswithin the substrates can favor the formation of the macrocycliccycloalkyne products. Representative examples are summarized in table 1and in the examples.

The diynes used as substrates may be conformationally pre-organized forthe ring closure by structural elements such as, e.g., chiral centers,hydrogen bonds, supramolecular structures, rigid backbones, coordinationat metal centers. Substrates which do not have any one of thesestructural elements and which are conformationally flexible for thisreason may be used as well. The substrates may be present in a supportedform.

Diynes with R₁, R₂≠H are preferred substrates. Especially preferredsubstrates are diynes in which the moieties R₁ and R₂ in schemes 2 and 3are selected such that a low-molecular alkyne R₁C≡CR₂ (e.g., 2-butyne,2-hexyne, 3-hexyne) is formed as a by-product of the formation of themacrocyclic cycloalkyne.

The reactions are performed such that the respective substrates arecontacted with the homogeneous or heterogeneous catalyst. Normally, thisis effected by mixing a solution or suspension of the substrate with asolution or suspension of the catalyst. Depending on the used catalystand substrate the reaction temperature can be varied, from −30° C. to+200° C. being preferably used. The reaction time is not critical andcan be varied between several minutes and several days. The reactionsare preferably performed under an inert atmosphere (e.g., argon,nitrogen, helium).

In general, hydrocarbons (e.g., hexane, octane, petroleum ether,toluene, xylenes, cumene, decalin) or halogenated hydrocarbons (e.g.,chlorobenzene, bromobenzene, fluorobenzene, trifluoromethylbenzene,dichlorobenzene, trichlorobenzene, tetrachloromethan,1,2-dichloroethane) are preferred as solvents for the ring-closing diynemetatheses yielding macrocyclic cycloalkynes. When selecting suitablecatalysts, other solvents such as, e.g., acetonitrile, tetrahydrofuran,1,4-dioxane, dimethoxyethane, dimethyl formamide, dimethyl sulfoxide,phenol may be used. Mixtures of said solvents may be used as well.

The reactions can be performed at pressures below atmospheric pressure.Applying a reduced pressure can result in the elimination of volatileby-products R₁C≡CR₂ and thus increase the obtained cycloalkyne yield.The reduced pressure applicable in each case depends on the specificproperties of the substrate, the formed cycloalkyne, the alkyne R₁C≡CR₂obtained as by-product according to schemes 2 and 3, the used solvent,and any additives. In addition, the low-molecular by-product R₁C≡CR₂ canbe stripped off the reaction mixture by passing an inert gas flowthrough the reaction mixture, which results in an increase of thecycloalkyne yield.

The recovery of the reaction mixtures and the purification of theproducts is not critical and depends on the respective physicalproperties of the produced products and/or the unreacted substrates.Preferred recovery and purification methods are distillation,sublimation, crystallization, chromatography, filtration, andextraction.

The macrocyclic cycloalkynes accessible according to the presentinvention may be used for the synthesis of numerous resultant products,e.g., by a reduction, oxidation, or cycloaddition of the triple bond andadditions to the triple bond. The possibility to convert the macrocycliccycloalkynes accessible by the present invention into macrocycliccycloalkenes having uniform configurations of the double bond bysuitable reactions (e.g., partial hydrogenation, hydrometalation,carbometalation) is particularly important.

Normally, macrocyclic cycloalkenes having a uniform configuration of thedouble bond are not accessible by a ring-closing metathesis (RCM) ofdienes. In most cases the RCM yields mixtures of the respective (E)- and(Z)-isomers with the (E) isomer being often formed preferably (SchusterM. et al., Angew. Chem. 1997, 109, 2125; Fürstner, A. Topics inCatalysis 1997, 4, 285; Fürstner, A. et al. Synthesis 1997, 792). Thepresent invention, however, enables the selective preparation ofmacrocyclic, (Z)-configured cycloalkenes by reacting the cycloalkynesobtained from the ring-closing metathesis of diynes using suitablereactions such as, e.g., a partial hydrogenation orhydrometalation/protonation (reviews: March, J. Advanced OrganicChemistry, 4th Ed., Wiley, New York, 1992, p 771ff; Marvell, E. N. etal. Synthesis 1973, 457; Fürstner, A. et al. J. Org. Chem. 1997, 62,2332). Here, the cycloalkynes accessible by the present invention caninitially be isolated and thereafter converted into the (Z)-configuredcycloalkene according to a suitable method. Alternatively, the formationof the macrocyclic cycloalkyne by a ring-closing alkyne metathesis of adiyne substrate and the conversion thereof into a macrocyclic,(Z)-configured cycloalkene in one single reaction batch is performedsuccessively within the meaning of an integrated chemical method.

Macrocyclic cycloalkenes having a (Z)-configured double bond are oftenused as antibiotics, pharmaceuticals for human or veterinary medicine,pheromones, odorous substances, perfume ingredients etc. Arepresentative example for the synthesis of a pharmaceutically relevantmacrocyclic product by oxidation of a macrocyclic cycloalkene areepothilone and analogues of this compound. If the (Z)-configuredcycloalkene required for the synthesis of epothilone or the analoguesthereof is prepared by RCM, usually (E)/(Z)-mixtures are obtained,however, only the respective (Z)-alkenes thereof can be converted intoepothilone or the analogues of this natural substance having the correctconfiguration of the stereogeneous centers of the formed epoxides byepoxidizing the double bond (Nicolaou, K. C. et al. Angew. Chem. 1996,108, 2554; Meng, D. J. Am. Chem. Soc. 1997, 119, 2733; Taylor, R. E.Tetrahedron Lett. 1997, 2061; Schinzer, D. et al. Angew. Chem. 1997,109, 543; Yang, Z. Angew. Chem. 1997, 109, 170; Bertinato, P. J. Org.Chem. 1996, 61, 8000; Nicolaou, K. C. et al. J. Am. Chem. Soc. 1997,119, 7960; Nicolaou K. C. et al. Nature 1997, 387, 268; Nicolaou, K. C.et al. Chem. Eur. J. 1997, 3, 1957; Nicolaou K. C. et al., Angew. Chem.1997, 109, 2181). Said synthesis and similar syntheses may be designedstereoselectively and consequently considerabely improved by forming themacrocyclic cycloalkyne and subsequently partially reducing saidcycloalkyne to the (Z)-cycloalkene.

The examples specified hereinafter describe prototypical ring-closingreactions of diynes to macrocyclic products by alkyne metathesiscatalysts under preferred conditions, however, said examples should byno means limit the scope, the scope of application, or the advantages ofthe present invention.

EXAMPLE 1 Cyclization of Hexanedicarboxylic Acid bis(3-pentynyl) Ester

In an apparatus consisting of a two-neck flask with an attacheddistillation bridge and a receiver cooled to −78° C., W(≡CCMe₃)(OCMe₃)₃(8 mg) is added to a solution of hexanedicarboxylic acid bis(3-pentynyl)ester (155 mg, 0.56 mmol) in 1,2,4-trichlorobenzene (30 ml). Theapparatus is evacuated to 20 mbar and the reaction mixture is heated to80° C. After 4 h additional W(≡CCMe₃)(OCMe₃)₃ (8 mg) is added, andthereafter the solution is stirred at 80° C./20 mbar for 13 h.Distilling off the solvent in the high vacuum and purifying the residueby column chromatography (eluent hexane/ethyl acetate 4:1) yields thecycloalkyne as colorless crystals (100 mg, 79%). Mp=106-107° C. ¹H NMR:δ=4.14 (t, 4H, J=5.5), 2.53 (t, 4H, J=5.6), 2.40 (m, 4H), 1.76 (m, 4H).¹³C NMR: δ=173.0, 77.8, 62.4, 34.8, 24.9, 19.0. MS, m/z (rel intensity):224 (<1), [M⁺], 179 (<1), 166 (1), 152 (1), 137 (1), 129 (3), 111 (7),101 (4), 78 (100), 66 (21), 55 (10), 41 (8). C₁₂H₁₆O₄ (224.3) calcd.: C64.24. H 7.18; found: C 64.14. H 7.15.

EXAMPLE 2 Cyclization of Hexanedicarboxylic Acid bis(3-pentynyl) Ester

A solution of hexanedicarboxylic acid bis(3-pentynyl) ester (105 mg) andW(≡CCMe₃)(OCMe₃)₃ (11 mg) in toluene (20 ml) is stirred under Ar at 80°C. for 1 h. The solvent is distilled off in the vacuum, the remainingresidue is purified by column chromatography (hexane/ethyl acetate 4/1),and the desired cycloalkyne is obtained in form of colorless crystals(59 mg, 69%). The analytical data are as specified in example 1.

EXAMPLE 3 Cyclization of Hexanedicarboxylic Acid bis(3-pentynyl) Ester

A solution of hexanedicarboxylic acid bis(3-pentynyl) ester (121 mg) andW(≡CCMe₃)(OCMe₃)₃ (12 mg) in chlorobenzene (20 ml) is stirred under Arat 80° C. for 2 h. The solvent is distilled off in the vacuum, theremaining residue is purified by column chromatography (hexane/ethylacetate 4/1), and the desired cycloalkyne is obtained in form ofcolorless crystals (70 mg, 73%). The analytical data are as specified inexample 1.

EXAMPLE 4 Cyclization and Cyclodimerization of 10-dodecyne-1-yl10-dodecynoate

A solution of 10-dodecyne-1-yl 10-dodecynoate (139 mg, 0.39 mmol) andW(≡CCMe₃)(OCMe₃)₃ (9 mg) in chlorobenzene (50 ml) is stirred at 80° C.for 10 h. After distilling off the solvent and a column chromatographyof the residue (hexane/ethyl acetate 20/1) the cycloalkyne is obtainedin form of colorless crystals (62 mg, 52%) and the cycloalkadiyne(cyclodimerization product) in form of a colorless, crystalline product.

Data of the cycloalkyne: ¹H NMR: δ=4.12 (t, 2H, J=5.8), 2.32 (t, 2H,J=6.8), 2.16 (m, 4H), 1.64 (m, 4H), [1.46 (m), 1.32 (m); 18H]. ¹³C NMR:δ=173.8, 80.7, 80.5, 63.9, 34.6, 29.39, 29.36, 29.2, 28.8 (2C), 28.6(2C), 28.4 (2C), 28.3, 28.1, 25.9, 25.3, 18.5, 18.4. MS, m/z (rel.intensity): 306 (35) [M⁺], 277 (4), 264 (5), 250 (3), 209 (6), 192 (19),178 (34), 164 (40), 149 (24), 135 (54), 121 (61), 107 (43), 95, (71), 81(97), 67 (98), 55 (100), 41 (82), 29 (25). C₂₀H₃₄O₂ (306.5) calcd.: C78.37. H 11.19; found: C 77.55. H 11.07.

Data of the cycloalkadiyne: ¹H NMR: δ=4.07 (t, 4H, J=6.6), 2.29 (t, 4H,J=7.4), 2.14 (m, 8H), 1.62 (m, 8H), 1.47 (m, 8H), 1.4-1.2 (36H). ¹³CNMR: δ=173.9, 80.27, 80.25, 64.3, 34.4, 29.3, 29.1, 29.06, 28.98, 28.96,28.88, 28.62, 28.57, 25.9, 25.0, 18.7. MS, m/z (rel. intensity): 612(99) [M⁺], 584 (7), 557 (5), 515 (6), 469 (5), 401 (8), 387 (11), 373(13), 359 (18), 345 (19), 147 (16), 135 (26), 121 (32), 107 (33), 95,(65), 81 (88), 67 (87), 55 (100).

EXAMPLE 5 Cyclization of N,N-bis(10dodecinoyl)ethane-1,2-diamine

A suspension of N,N-bis(10dodecinoyl)ethane-1,2-diamine (142 mg, 0,34mmol) and W(≡CCMe₃)(OCMe₃)₃ (8 mg) in chlorobenzene (20 ml) is stirredat 80° C. for 3 h. After distilling off the solvent the cycloalkyne isobtained. An analytically pure sample is obtained by extracting thecatalyst out of the product. MS m/z (rel. intensity): 362 (82) [M⁺], 334(17), 319 (9), 303 (8), 279 (7), 265 (7), 249 (9), 237 (16), 221, (22),206 (14), 178 (13), 168 (13), 154 (10), 135 (14), 126 (10), 95 (40), 81(51), 67 (67), 55 (91), 44 (79), 41 (73), 30 (100).

EXAMPLE 6 Cyclization of Hexanedicarboxylic acid bis(3-pentynyl) Esterin THF

A solution of hexanedicarboxylic acid bis(3-pentynyl) ester (89 mg) andW(≡CCMe₃)(OCMe₃)₃ (18 mg) in tetrahydrofuran (15 ml) is refluxed underAr for 22 h. The solvent is distilled off in the vacuum, the remainingresidue is purified by column chromatography (hexane/ethyl acetate 4/1),and the desired cycloalkyne is obtained in form of colorless crystals(46 mg, 64%). The analytical data are as specified in example 1.

EXAMPLE 7 Cyclization of Hexanedicarboxylic Acid bis(3-pentynyl) EsterUsing W(≡CPh)(OCMe₃)₃

A solution of hexanedicarboxylic acid bis(3-pentynyl) ester (271 mg) andW(≡CPh)(OCMe₃)₃ (25 mg) in toluene (30 ml) is heated under Ar at 80° C.for 1 h. The solvent is distilled off in the vacuum, the remainingresidue is purified by column chromatography (hexane/ethyl acetate 4/1),and the desired cycloalkyne is obtained in form of colorless crystals(134 mg, 61%) The analytical data are as specified in example 1.

EXAMPLE 8 Cyclization by Using Mo(CO)₆/p-chlorophenol as AlkyneMetathesis Catalyst

A solution of the diyne substrate 1 (200 mg), Mo(CO)₆ (5 mg), andp-chlorophenol (55 mg) in chlorobenzene (75 ml) is heated to 120° C. for3 h. During the reaction a slight argon flow is passed through thereaction mixture. In order to recover the product, the volatilecomponents are distilled off under vacuum and the remaining residue ispurified by column chromatography (hexane/t-butyl methyl ether 20/1).The 30-membered cycloalkyne 2 is obtained in form of a colorless solid(126 mg, 70%).

¹H-NMR: δ=5.63 (dt, 2H), 4.01 (t, 4H), 3.00 (dd, 4H, J=4, 1.6), 2.08 (t,4H, J=6.5), 1.36 (m, 8H), 1.23 (m, 18H). ¹³C-NMR: δ=171.8, 126.3, 80.8,65.2, 38.6, 29.7, 29.6, 29.5, 29.4, 29.1, 28.9, 28.8, 26.2, 19.0.

EXAMPLE 9 Preparation of Ambrettolide by a Diyne Metathesis and aSubsequent Partial Hydrogenation

A solution of the diyne 3 (1.0 g), Mo(CO)₆ (42 mg), and p-chlorophenol(425 mg) in chlorobenzene (150 ml) is heated to 120° C. for 19 h. Duringthe reaction a slight argon flow is passed through the reaction mixturefrom a gas inlet. In order to recover the product, the volatilecomponents are distilled off under vacuum and the remaining residue ispurified by column chromatography (eluent hexanelt-butyl methyl ether20/1). The cycloalkyne 4 is obtained as a colorless syrup (568 mg, 69%)with the following analytical data:

¹H-NMR: δ=4.10 (t, 2H, J=5.2), 2.28 (t, 2H, J=7), 2.13 (m, 4H), 1.60 (m,4H), 1.15 (m, 14H). ¹³C-NMR: δ=174.4, 80.7, 80.6, 64.3, 35.0, 28.8,28.7, 28.5, 28.46, 28.40, 27.4, 25.3, 19.1, 18.9.

A reaction mixture consisting of the cycloalkyne 4 (154 mg), quinoline(60 μl), and Lindlar catalyst (=5% Pd on calcium carbonate, contaminatedwith lead) (60 mg) in hexane (3 ml) is stirred under an hydrogenatmosphere (1 atm) for 1.5 h. The catalyst is filtered off, the filtrateis washed with aqueous HCl (5%), the organic phase is dried over Na₂SO₄,and the solvent is removed in the vacuum. A subsequent columnchromatography (eluent hexane/t-butyl methyl ether 20/1) yieldsabrettolide 5 (138 mg, 92%).

¹³C-NMR: δ=174.3, 130.5, 130.4,64.1, 34.9, 29.8, 29.1, 29.0,28.9, 28.8,28.7, 28.0, 27.3, 27.1, 25.7, 25.6.

EXAMPLE 10 Cyclization of Hexanedicarboxylic Acid bis(3-pentynyl) EsterUsing Mo[N(t-Bu)(3,5-C₆H₃Me₂)]₃/CH₂Cl₂ as Diyne Metathesis Catalyst

A reaction mixture consisting of hexanedicarboxylic acid bis(3-pentynyl)ester (60 mg) and Mo[N(t-Bu)(3,5-C₆H₃Me₂)]₃ (13.5 mg) (preparedaccording to the literature: C. E. Laplaza et al. J. Am. Chem. Soc.1996, 118, 8623) in toluene (15 ml) and CH₂Cl₂ (50 μl) is heated underargon for 19 h. The solvent is distilled off in the vacuum, theremaining residue is purified by column chromatography (hexane/ethylacetate 4/1) and the desired cycloalkyne is obtained in form ofcolorless crystals (38.8 mg, 80%). The analytical data are as specifiedin example 1. Instead of CH ₂Cl₂ also CHCl₃, CCl₄, CH₂Br₂, CH₂I₂,α,α-dichlorotoluene, or trimethylchlorosilane can be used to activatethe molybdenum component. Similarly, the reaction can be performed indichloromethane as the solvent.

EXAMPLE 11 Diyne Metathesis Using Mo[N(t-Bu)(3,5-C₆H₃Me₂)]₃/CH₂Cl₂

A reaction mixture consisting of diyne 6 (91.5 mg) andMo[N(t-Bu)(3,5-C₆H₃Me₂)]₃ (20.2 mg) (prepared according to theliterature: C. E. Laplaza et al. J. Am. Chem. Soc. 1996, 118, 8623) intoluene (15 ml) and CH₂Cl₂ (50 μl) is heated to 80° C. under argon for22 h. The solvent is distilled off in the vacuum, the remaining residueis purified by column chromatography (hexane/ethyl acetate 8/1) and thedesired cycloalkyne 7 is obtained in form of a colorless syrup (62 mg,84%). Analytical data:

¹H NMR: δ=4.28 (t, 4H, J=5.4), 3.43 (s, 4H), 2.49 (t, 4H). ¹³C NMR:δ=169.4, 78.1, 62.9, 34.6 (2×), 19.6. MS: m/z (rel. intensity): 228 (56,[M⁺]), 78 (100).

EXAMPLE 12 Diyne Metathesis Using Mo[N(t-Bu)(3,5-C₆H₃Me₂]₃/CH₂ Cl₂

A reaction mixture consisting of diyne 8 (511 mg) andMo[N(t-Bu)(3,5-C₆H₃Me₂)]₃ (104.4 mg) (prepared according to theliterature: C. E. Laplaza et al. J. Am. Chem. Soc. 1996, 118, 8623) intoluene (82 ml) and CH₂Cl₂ (160 μl) is heated to 80° C. under argon for20 h. The solvent is distilled off in the vacuum, the remaining residueis purified by column chromatography (hexane/ethyl acetate 4/1) and thedesired cycloalkyne 9 is obtained in form of a colorless syrup (369 mg,88%). Analytical data: ¹H NMR: δ=8.76 (dd, 1 H, J=4.9, 1.9), 8.12 (dd, 1H, J=7.9, 1.5), 7.52 (dd, 1 H, J=4.9), 4.63 (t, 2H, J=5.5), 4.42 (t, 2H,J=5.6), 2.57 (m, 4H). ¹³C NMR: δ=166.1, 165.8, 151.1, 151.0, 137.1,128.7, 125.1, 79.2, 78.8, 63.4, 63.1, 20.0, 19.4). MS: m/z (rel.intensity): 245 (2, [M⁺]), 78 (100).

EXAMPLE 13 Preparation of a 11-membered Cycloalkyne: Cyclization andCyclodimerization of Dimethylmalonic Acid bis(3-pentynyl) Ester

A solution of dimethylmalonic acid bis(3-pentynyl) ester 10 (262 mg) andW(≡CCMe₃)(OCMe₃)₃ (28 mg) in chlorobenzene (60 ml) is stirred underargon at 80° C. for 1 h. After distilling off the solvent at 12 mbar anda purification by of the residue column chromatography the waxycycloalkyne 11 (97 mg, 47%) and crystalline cycloalkadiyne 12 (87 mg,42%) is obtained and a small amount of Diyne 10 (37 mg, 14%) isrecovered.

Data of the cycloalkyne 11: ¹H NMR: δ=4.29 (t, 4H, J=5.8), 2.43 (t, 4H),1.43 (s, 6H). ¹³C NMR: δ=172.0, 79.8, 61.8, 50.0, 22.1, 19.7,.−MS, m/z(rel. intensity): 152 (2) [M−58], 137 (3), 111 (5), 87 (5), 78 (100), 70(49), 66 (17), 65 (18), 41 (16).-C₁₁H₁₄0₄ (210.2) calcd: C 62.85. H6.71; found: C 63.01. H 6 67.

Data of the cycloalkadiyne 12: ¹H NMR: δ=4.15 (t, 8H, J=6.8), 2.53 (t,8H), 1.43 (s, 12H). ¹³C NMR: δ=172.4, 77.3, 63.5, 49.4, 22.5, 18.8.−MS,m/z (rel. intensity): 420 (5) [M⁺], 174 (8), 156 (48), 141 (14), 115(7), 87 (10), 78 (100), 70 (34), 69 (31), 66 (13), 65 (11), 41 (19).

TABLE 1 Synthesis of functionalized, macrocyclic cycloalkynes by ring-closing metathesis of diynes using W(≡CCMe₃)(OCMe₃)₃ as a catalyst.Substrate Product Yield

52%

79%

69%

52%

97%

>90%

52%

55%

20%

What is claimed is:
 1. A process for the preparation of a carbocyclic orheterocyclic compound having 9 or more ring atoms by a ring-closingmetathesis reaction, said process comprising reacting one or more diynesubstrates in a reaction medium in the presence of one or several alkynemetathesis catalysts present homogeneously or heterogeneously in thereaction medium.
 2. The process according to claim 1, which produces acarbocyclic or heterocyclic compound having 12 or more ring atoms. 3.The process according to claim 1, wherein the one or more diynesubstrates contain one or several functional groups in the form ofsubstituents on the chain or heteroatoms within the chain; saidfunctional groups comprise branched or unbranched alkyl moieties,aromatic or non-aromatic carbocyclic rings, aromatic or non-aromaticnitrogen, oxygen, sulfur or phosphorus containing heterocyclic rings,carboxylic acids, esters, ethers, epoxides, silyl ethers, thioethers,thioacetals, disulfides, alcohols, anhydrides, imines, silyl ethers,silylenol ethers, ammonium salts, amines, amides, nitriles,perfluoroalkyl groups, gem-dialkyl groups, alkenes, halogens, ketones,ketals, aldehydes, acetals, carbamates, carbonates, urethanes, ureas,sulfonates, sulfones, sulfonamides, sulfoxides, phosphates,phosphonates, nitro groups, organosilane moieties, or metal centers. 4.The process according to claim 1, wherein the alkyne metathesis catalystused is a transition metal alkylidyne complex.
 5. The process accordingto claim 4, wherein the transition metal alkylidyne complex is formed insitu within the reaction medium.
 6. The process according to claim 4,wherein the transition metal alkylidyne complex used as the catalyst isa compound of the type M(≡CR¹)(OR²)₃, wherein: M=Mo, or W; R¹=C₁-C₂₀alkyl, aryl, alkenyl, alkylthio, or dialkylamino; and R²=C₁-C₂₀ alkyl,or aryl.
 7. The process according to claim 6, wherein: M=W R¹=CMe₃, orPh; and R²=CMe₃, CH(CF₃)₂, CMe₂CF₃, CMe(CF₃)₂, C(CF₃)₃, C₆H₃Me₂,C₆H₃i-Pr₂, or C₆H₃t-Bu₂.
 8. The process according to claim 4, whereinthe transition metal alkylidyne complex used as the catalyst is acompound of the type Re(≡CR¹)(═NAr)(OR²)₂, wherein: R¹=C₁-C₂₀ alkyl,aryl, or alkenyl; Ar=C₆-C₂₀ aryl; and R²=C₁-C₂₀ alkyl, or aryl.
 9. Theprocess according to claim 8, wherein: R¹=CMe₃, or Ph; Ar=C₆-C₂₀ aryl;and R²=CMe₃, CH(CF₃)₂, CMe₂CF₃, CMe(CF3), C(CF₃)₃, C₆H₃Me₂, C₆H₃i-Pr₂,or C₆H₃t-BU_(2.)
 10. The process according to claim 1, wherein thealkyne metathesis catalyst used is a complex having a metal≡metal triplebond.
 11. The process according to claim 10, wherein the alkynemetathesis catalyst used is a complex of the type (RO)₃M≡M(OR)₃,wherein: M=Mo, or W; and R=C₁-C₂₀ alkyl.
 12. The process according toclaim 11, wherein: R=CMe₃, CH(CF₃)₂, CMe₂CF₃, CMe(CF₃)₂, or C(CF₃)₃. 13.The process according to claim 1, wherein the alkyne metathesis catalystis formed from M[N(R¹)Ar]₃ and a halogen compound of the type R² ₂EX₂ orR³ ₃ SiX; wherein: M=Mo, or W; R¹=C₁-C₂₀ alkyl, sec-alkyl, t-alkyl, orcycloalkyl; Ar=C₆-C₂₀ aryl; R²=H, F, Cl, Br, I, C₁₋₂₀ alkyl, or aryl;E=C, or Si; R³=C₁-C₂₀ alkyl, or aryl; and X=F, Cl, Br, or I.
 14. Theprocess according to claim 13, wherein: M=Mo; R¹=t-Bu, or i-Pr; Ar=C₆H₅,C₅H₄Me, C₆H₃Me₂, C₆H₃(iPr)₂, C₆H₃(t-Bu)₂, or C₆H₂Me₃; R²=H, F, Cl, Br,I, or C₆CH₅; and R³=Me, t-Bu, or i-Pr.
 15. The process according toclaim 1, wherein the one or more diyne substrates are conformationallypre-organized for the ring closure by one or several structuralelements; and said structural elements comprise chiral centers, hydrogenbonds, supramolecular structures, rigid backbones, or a coordination tometal centers.
 16. The process according to claim 1, wherein the one ormore diyne substrates are conformationally flexible.
 17. The processaccording to claim 1, wherein the one or more diyne substrates are usedin a supported form.
 18. The process according to claim 1, whichproduces a macrocyclic cycloalkyne, and wherein the formation of themacrocyclic cycloalkyne is favored by selecting the concentration of theone or more diyne substrates in solution.
 19. The process according toclaim 1, wherein the reaction is carried out at a pressure belowatmospheric pressure.
 20. The process according to claim 1, wherein sideproducts are eliminated by passing an inert gas flow through thereaction medium.
 21. The process according to claim 1, wherein theactivity of the catalyst or catalysts used is increased by additives.22. The process according to claim 21, wherein phenols, geminaldihalogenalkanes (gem-dihalogenalkanes) or halogensilanes are used asadditives.
 23. The process according to claim 22, wherein phenol,trifluoromethylphenol, bis(trifluoromethyl)phenol, fluorophenol,difluorophenol, pentafluorophenol, chlorophenol, dichlorophenol,pentachlorophenol, dichloromethane, dibromomethane, diiodomethane,chloroform, bromoform, iodoform, tetrachlorocarbon, tetrabromocarbon,tetraiodocarbon, α, α-dichlorotoluene, trimethylchlorosilane,dimethyldichlorosilane, trimethylbromosilane,dimethyl(t-butyl)chlorosilane, or dimethylphenylchlorosilane are used asadditives.
 24. The process according to claim 1, wherein the one or morediyne substrates are cyclodimerized.
 25. A process for the preparationof a carbocyclic or heterocyclic cycloalkene having 9 or more ringatoms, said process comprising preparing a cycloalkyne according to theprocess according to claim 1, and selectively converting saidcycloalkyne into a cycloalkene having a uniform double bondconfiguration.
 26. The process according to claim 25, which produces acycloalkene having a (Z)-configured double bond.
 27. A process for thepreparation of epothilone or an epothilone analog, said processcomprising preparing a functionalized cycloalkyne according to theprocess according to claim 2 and thereafter converting saidfunctionalized cycloalkyne into epothilone or an epothilone analog. 28.The process according to claim 1, wherein the carbocyclic orheterocyclic compound produced is one of antibiotics, pharmaceuticalsfor human or veterinary medicine, pheromones, crown ethers, odoroussubstances, perfume ingredients, or flavoring agents.
 29. The processaccording to claim 1, wherein the alkyne methathesis catalyst is aMo-carbonyl complex.
 30. The process according to claim 29, wherein theMo-carbonyl complex is Mo(CO)₆.